Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - ITCC-P4 (ITCC Pediatric Preclinical POC Platform – Sofia ref.: 116064)

Teaser

Cancer remains the leading cause of disease-related death in children after the first year of life. For the ~25% of children who experience relapses of their malignant solid tumours, curative treatment options are scarce. Preclinical drug testing to identify promising...

Summary

Cancer remains the leading cause of disease-related death in children after the first year of life. For the ~25% of children who experience relapses of their malignant solid tumours, curative treatment options are scarce. Preclinical drug testing to identify promising treatment options that match tumour biology is hampered by the fact that i) molecular genetic data on paediatric solid tumours from relapsed patients and thus our understanding of tumour evolution and therapy resistance are very limited to date and ii) for many of the high-risk entities, no appropriate and molecularly well characterized patient-derived models and/or genetic mouse models are available. Thus, quality-assured upfront preclinical testing of novel molecularly targeted compounds in a (saturated) repertoire of well-characterized models will establish the basis to increase therapeutic successes of these drugs in children with solid malignancies. Since these tumours are overall genetically much less complex than their adult counterparts, it is anticipated that it will be easier to identify powerful predictive biomarkers to allow for accurate matching of targets and drugs. To address the significant preclinical gap in identifying promising molecules to fight paediatric cancer, the main objectives for this preclinical platform project are to:
• Establish a representative collection of patient-derived in vitro and in vivo models (PDX and genetic mouse models) (~400) of the most common paediatric solid high-risk entities including a significant proportion of models from relapses.
• Molecularly characterize and to quality-assess the models as well as the matching of primary tumour samples and germline controls with state-of-the-art molecular diagnostic tools.
• Enable regulatory filings in the EU through the development of comprehensive preclinical data packages necessary to move drugs into clinical trials for children with solid tumours.
• Prioritize paediatric drug development using existing collections of molecular data for systematic target reports, followed by in vivo drug testing in faithful disease models including pharmacokinetics and pharmacodynamics where necessary (e.g., brain penetration
• Build an international consensus on minimal preclinical data packages for paediatric cancer to enable clinical development.
• Identify suitable biomarkers for future clinical stratification of patients.
Ultimately, the establishment of the ITCC-P4 platform will overcome a long-standing gap by enabling thorough molecular characterization of high-risk paediatric malignancies coupled with standardized preclinical testing procedures, and will thus greatly expedite the development of more precise and efficacious drugs.

Work performed

Excellent cooperation continues between academia and EFPIA in all work packages. TheITCC-P4 website and LinkedIn allow facile connection with the community and were consistently updated. A key aspect of platform development is informed consent, documents for which are now in place for the majority of centres. As a result, model development is underway and PDX models developed specifically for this platform have been delivered, as well as models from external sources (Seattle Children’s Hospital) and are currently being expanded and characterized. Molecular characterization of the models and tumour material/blood was also initiated. At Bayer, full imaging proof-of-concept evaluation was performed on one brain tumour model, which will serve as the focal point for expanded imaging analyses. In 2018, Roche received four neuroblastoma models from the testing centers along with immune profiling data from the Charité (which will serve as baseline data for the development of these models in humanized mice). Regarding in vitro organoid model development, neuroblastoma organoids were established while medulloblastoma organoid establishment remained elusive. Information technology advances have continued as evidenced by an enhanced mouse tumor barcoding system and continued development of the R2 platform. The consortium achieved consensus on dosing regimens for drugs chosen for efficacy testing. To support selection, prioritization and planning of targeted molecule efficacy testing, the methodology required for the determination of “target actionability” was established, resulting in a draft manuscript. As part of our outreach to the paediatric community, we hosted two high profile, international events. The first, at the request of the AACR, was to jointly host a half day event at the AACR in Chicago with leadership from the Paediatric Preclinical Testing Consortium of the US National Cancer Institute. This meeting highlighted the two platforms and set the stage for collaboration between activities in North America and the EU, including the harmonization of research practices and data sharing. The second event was a highly successful international symposium in Amsterdam whose goal was to reach an international consensus on the role and place of preclinical evaluation on paediatric tumor models. This meeting included representatives from major EU and US paediatric centers, PPTC, FDA, patient advocacy and EU citizens. From the meeting, a “white paper” was initiated and will be published in a peer reviewed journal. This document, the first of its kind for global paediatric research, will serve as the basis for a guidance document to be submitted to regulatory authorities for qualification to improve prioritization and effectiveness of paediatric. Outreach to the broader IMI community occurred with two junior investigators being selected to present their work at the IMI anniversary in Brussels. Numerous disclosures from members of the Leadership team were given across the globe as part of our ongoing effort to inform the worldwide paediatric community. Finally, regarding WP7 a plan is now in place to discuss development of the sustainability platform.

Final results

Progress remains limited to planned activities in the immune oncology space (infrastructure identified, neuroblastoma and rhabdomyosarcoma models currently being developed), and the development of tumour organoids not currently available in the public domain (in particular, brain tumor). The humanized models under development at Roche will be a major leap forward for the field. From a social standpoint, the importance of ITCC-P4 is demonstrated by our growing profile in the public space. The need for public-private partnerships in defeating paediatric cancer is a topic of considerable interest across all stakeholders. ITCC-P4, through presentations such as ACCELERATE and the Annual Workshop of the European Network of Paediatric Research, and an invited presentation at the 2018 AACR meeting in Chicago, has established a reputation as a model for private-public partnership. The well-attended and highly regarded Amsterdam symposium is an example of ITCC-P4 leveraging its collective research and policy talents to bring together groups that in the past remained distant and essentially non collaborative.

Website & more info

More info: https://www.itccp4.eu/.